Succinimide racemization

Radkiewicz et al.184 explored the mechanism of aspartic acid racemization by means of the DFT(B3LYP)/SCRF calculations. The DFT/SCRF calculations provided quantitative rationalization of the rapid racemization observed at succinimide residues in proteins. The proposed reaction mechanism was supported by the computed increase of the acidity of the succinimide residue in aqueous solution compared to gas phase. 

T. Geiger, S. Clarke, Deamidation, Isomerization, and Racemization at Asparaginyl and Aspartyl Residues in Peptides Succinimide-Linked Reactions That Contribute to Protein Degradation , J. Biol. Chem. 1987, 262, 785 - 794. 

Geiger T. and Clarke S. (1987), Deamidation, isomerization and racemization at asparaginyl and aspartyl residues in peptides. Succinimide-linked reactions that contribute to protein degradation, J. Biol. Chem. 262, 785-794. 

Scheme 61, yielded thiazole 200 as the major product, along with minor amounts of carbinol 201 [152]. On the other hand, treatment of the imine formed from 199 and p-methoxyphenylamine with catalytic tetrabutylammonium cyanide, produced suc-cinimide derivative 202. In both cases, the process is initiated by nucleophilic attack to the carbaldehyde C=0 (or azomethine s C=N) group, which is followed up by an anionic rearrangement. A variation of the above process using as catalysts /V-heterocyclic carbenes (NHC) derived from base treatment of azolium, imidazo-lium, or triazolium salts, has also been developed to access gem-disubstituted succinimides [153, 154]. Unfortunately, an attempt of kinetic resolution of racemic 4-formyl (3-lactams by using chiral NHC resulted in moderate selectivities only [154]. 

In a racemization reaction, the configuration about the a-carbon of the amino acid is inverted. For Asn and Gin amino acids, the racemization is facilitated by enolization of the succinimide, as shown in Figure 133. 

Analytical Properties Higher selectivity for nitrogen-containing racemates than fl-/V-(3,5-dinitrobenzoyl) phenylglycine examples of nitrogen-containing racemates include succinimides, hydantoins, and mandelates Reference 41... 

The racemic product mixture of Step 4 was also prepared using succinimide (2) as illustrated in Eq.l and described below by the author ... 

Allylsilane 59 was obtained by initial reaction of the succinimide 55 with the corresponding Grig-nard alkylsilane and a subsequent simple sequence of reactions. This allylsilane was readily cyclized in formic acid at room temperature to 60, which was subjected to a Wacker oxidation (Tsuji 1984) to afford the dihydroanatoxin-a derivative 28. The nitrogen deprotection step with iodotrimethylsilane (Melching et al. 1986) funushedthe ( )-dihydroanatoxin-a, which was reprotected with oc according to the previously discussed Rapoport methodology (Sardina et al. 1989) to furnish the racemic ( )-anatoxin-a. The overall yield of this synthesis was 7% from the succinimide. 

Preparative Methods N-t-Boc- and Al-Cbz-3-bromo-5,6-diphenyl-2,3,5,6-tetrahydrooxazin-2-ones are not commercially available. They are prepared by addition of 1 equiv of N-Bromosuccinimide to a solution of the parent oxazinone (commercially available as the individual enantiomers or as racemates) in CCI4 at reflux. Upon cooling of the reaction mixture to 0 °C and filtering off the succinimide, the CCI4 is removed under reduced pressure and the bromooxazinone is obtained in essentially quantitative yield as a white solid and is used without further purification. ... 

Active Esters. The synthesis of reactive esters of acylamino acids and their use in lengthening a peptide chain by reaction at the amino end is a justifiably popular method racemization is avoided, yields are good, and purification of the products is relatively easy. Esters of N-hydroxy-succinimide (l), N-hydroxypiperidine (ll) and 8-hydroxyquinoline (III) have received particular attention during I966. 

In 2007, You and co-workers found the readily available NHC effieiently catalyzes the ring expansion of 4-formyl-o-lactams. This organoeatalytie process affords succinimide derivatives smoothly, featuring ready availability of the catalyst, low catalyst loading, and mild reaction conditions. Subsequently, they carried out a study on the kinetic resolution of raeemie 4-formyl-a-lactams by chiral NHC. With 5 mol% of the optimized ehiral eatalyst, kinetic resolution of racemic 4-formyl-a-lactams gave (+)-sueeinimide derivatives in 26-50% yield with up to 44% ee and alcohols derived from starting materials in 39-49% yield with up to 99% ee (Scheme 7.87). 

Najera and coworkers [34] used a commercial poly(styrene-a/f-maleic anhydride) copolymer as support material. The copolymer was first reacted with hydroxylamine and then converted to a polymer-supported N-hydroxy succinimide. The product was then used in a peptide-coupling reactions. Low levels of racemization were reported. Addition of hexane allowed the removal of the polymeric material by filtration. 

We used a synthetic polypeptide, a,P-poly[N-(2-hydroxyethyl)-D,L-aspartamide], which was prepared by aminolysis with aminoethanol of D,L-poly uccinimide obtained by thermal polycondensation The polysuccinimide is fully racemic and the aminolysis results in random opening of the succinimide rings, as demonstrated by the C-NMR spectrum As enzymes hydrolyze only the peptide bond... 

In the dicyclohexylcarbodi-imide method of peptide-bond formation, the problems of racemization and rearrangement to A-acylureas can be avoided by interception of the intermediate activated ester with 1-hydroxybenzo-triazole. The ester so produced functions efficiently in amide-bond formation similar beneficial properties have already been noted with iV-hydroxy-succinimide. 

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